Cardiac Dysfunction in the Met Syndrome: Cross-talk between IR and bAR Signaling

Met 综合征中的心脏功能障碍：IR 和 bAR 信号传导之间的串扰

• 批准号: 9272923
• 负责人: E Dale Abel
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272923
• 关键词: ADRBK1 gene; Acute; Address; Adenylate Cyclase; Adrenergic Agents; Affect; Animals; Apoptosis; Attenuated; Biosensor; California; Cardiac; Cardiac Myocytes; Cardiomyopathies; Chronic; Collaborations; Complex; Coupling; Cross Syndrome; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Diet; Fatty acid glycerol esters; Functional disorder; Gene Targeting; Generations; Genetic; Genetic Transcription; Glucose Intolerance; Goals; Heart; Heart failure; Human; Hyperinsulinism; Hyperlipidemia; Hypertrophy; IRS1 gene; Impairment; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Iowa; Isoproterenol; Knock-out; Laboratories; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Molecular; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Phosphorylation; Physiological; Population; Prevention; Production; Proteins; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; United States; Universities; Ventricular; Ventricular Remodeling; Yang; base; constriction; desensitization; epidemiology study; glucose uptake; in vivo; insulin sensitivity; insulin signaling; mortality; mouse model; mutant mouse model; novel; phosphodiesterase IV; phospholamban; pressure; prevent; protein degradation; public health relevance; response; trafficking; type I diabetic; western diet

DESCRIPTION (provided by applicant): Obesity, type 2 diabetes (T2DM) and insulin resistance are independent risk factors for heart failure, which affects a rapidly increasing segment of the US population. The long-term goal of this proposal is to understand the mechanisms linking these metabolic disorders and left ventricular (LV) dysfunction prior to and in concert with heart failure. Obesity is associated with insulin resistance, hyperlipidemia, glucose intolerance and hyperinsulinemia. Epidemiological studies suggest that hyperinsulinemia is an independent risk factor for heart failure. In humans and mouse models, the heart may retain its insulin sensitivity in terms of insulin's ability to activate IRS1, PI3K ad Akt signaling, despite insulin resistance in other organs such as the liver and skeletal muscle. This hyperinsulinemia also accelerates adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes �R-mediated stimulation of cardiac contractility, which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal, will therefore focus on the hypothesis that hyperinsulinemia might attenuate LV contractility by directly impairing �or �-adrenergic (�) signaling. Specifically, activation of cardiomyocyte insulin receptors (IR) in hyperinsulinemic states, impairs � signaling via two distinct mechanisms: (1) Increased �R/Gi coupling that inhibits adenylyl cyclase and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California -Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling will address this hypothesis in the following two specific aims. Aim 1 (Xiang). Will define the molecular mechanisms by which insulin impairs � signaling in cardiomyocytes by testing the following hypotheses: Insulin signaling increases �R/Gi coupling via a complex containing �R, IR, IRS, and GRK2 that inhibits adenylyl cyclase-mediated cAMP generation. Insulin signaling enhances cardiac PDE4 levels via �R-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel). Will determine the physiological consequences of �-IR interactions in hearts in vivo by testing the hypotheses that: Acute or chronic hyperinsulinemia will impair myocardial � signaling and reduce contractility or inotropic reserve and that hyperinsulinemia in obesity, T2DM and heart failure will exacerbate cardiac dysfunction by impairing inotropic reserve. By using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or � signaling, we will dissect the mechanism for IR-� crosstalk that limits myocardial contractility in insulin resistant states.

描述（由适用提供）：肥胖，2型糖尿病（T2DM）和胰岛素抵抗是心力衰竭的独立危险因素，这会影响美国人群的迅速增加。该提案的长期目标是了解将这些代谢性疾病和左心室（LV）功能障碍联系起来和与心力衰竭协同的机制。肥胖与其他器官（如肝脏和骨骼肌）中胰岛素抵抗，高脂血症，葡萄糖耐含量和抗胰岛素耐药性有关。这种高胰岛素疾病还可以加速AD LV重塑在压力超负荷肥大和心肌细胞中胰岛素信号传导的降低，从而限制了肥厚的重塑，并降低了压力超负荷的凋亡，从而保留LV功能。我们最近的研究表明，高胰岛素血症使R介导的心脏收缩率脱敏，这代表了一种连接胰岛素抵抗，高胰岛素血症和LV功能障碍的新机制。因此，该提案将集中于以下假设：高胰岛素血症可能通过直接损害``或肾上腺素（肾上腺素）信号来减弱LV收缩性。具体而言，高胰岛素态中心肌细胞胰岛素受体（IR）的激活会损害通过两种不同的机制信号传导：（1）抑制腺苷酸环化酶和cAMP产生的R/GI耦合增加，以及（2）增加PDE4D的表达，从而增加了CAMP DENGRADADITICARCAMC。该多PI提案反映了埃文·戴尔·阿贝尔（Evan Dale Abel）（爱荷华大学）和杨·凯文·徐（Yang Kevin Xiang）（加利福尼亚大学 - 达维斯大学）实验室的积极合作。我们在心肌胰岛素信号传导和心肌肾上腺素信号传导方面的综合专业知识将在以下两个具体目标中解决这一假设。目标1（Xiang）。将定义胰岛素通过测试以下假设来损害心肌细胞的信号的分子机制：胰岛素信号通过含有r/r，IR，IRS和GRK2的复合物增加r/gi偶联，从而抑制adenylyl Cyclase Cyclase Cyclase介导的营地生成。胰岛素信号传导通过PDE4转录和蛋白质更新的R-ERK依赖性调制来增强心脏PDE4水平。目标2（亚伯）。将通过测试：急性或慢性高胰岛素血症的假设来确定体内心脏中IR相互作用的身体后果，这会损害心肌信号，并降低收缩性或肌力储备以及肥胖症，T2DM和心脏故障的高胰岛素血症，而心脏衰竭会通过耐药化的效果降低心脏衰竭。通过使用新型的分子生物传感器来定义心肌细胞中的亚细胞肾上腺素信号传导域，以及具有扰动的IR或信号传导的全面的突变小鼠模型，我们将剖析IR-串扰的机制，以限制胰岛素抵抗状态的心肌收缩性。